The interplay of UV and cutaneous papillomavirus infection in skin cancer development.

Daniel Hasche,Julita Mikulec,Sabrina E Vinzón,Sonja Stephan,Christa Flechtenmacher,Ilona Braspenning-Wesch,Baki Akgül,Martina Niebler,Frank Rösl,Hermann-Josef Gröne

doi:10.1371/journal.ppat.1006723

Abstract

Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored—like in humans—Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.

Highlights

More than 20% of all human cancers have an infectious etiology [1]
Since the viral DNA is frequently lost during progression from precursor lesions to non-melanoma skin cancer (NMSC)—which is in contrast to high-risk mucosal human papillomaviruses (HPVs) in the context of anogenital cancer—their etiological role is still controversially discussed
We provide the first evidence that only the cooperation between UVB and cutaneous papillomavirus infection strongly favors the development of skin tumors in the natural model Mastomys coucha

Summary

Introduction

More than 20% of all human cancers have an infectious etiology [1]. In the case of anogenital cancer, high-risk human papillomaviruses (HPVs) of genus alpha (α-HPVs) were identified to be necessary and sufficient to induce cervical cancer [2]. Still controversially discussed, there is increasing evidence that infection with certain cutaneous HPVs of genus beta (β-HPVs)—in conjunction with UV exposure—is a crucial factor in the development of non-melanoma skin cancer (NMSC) and, squamous cell carcinoma (SCC) [3]. The risk of OTRs to get a SCC increases up to 250-fold upon iatrogenic immunosuppression in comparison to the healthy population [5] and the frequency of tumor formation correlates with the extent and duration of immunosuppression [6]. It is estimated that up to 40% of OTRs will develop basal cell carcinomas (BCCs) and SCCs within the first 10 years after transplantation, and up to 80% after 20 years [8]. The proof of a causal link between cutaneous PV infection and NMSC would support the concept of a broader vaccination strategy, eliminating at least one important cofactor of skin carcinogenesis [9]

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Conclusion